Mi Jin Kim

Infliximab therapy in children with Crohn’s disease: a one‐year evaluation of efficacy comparing ‘top‐down’ and ‘step‐up’ strategies

Background:u2002 The aim of this study was to evaluate the efficacy of ‘top‐down’ regimens for the treatment of paediatric Crohn’s disease (CD) and to compare it with the effects of ‘step‐up’ treatment.

Infliximab "Top-Down" Strategy is Superior to "Step-Up" in Maintaining Long-Term Remission in the Treatment of Pediatric Crohn Disease.

Objectives: We aimed to compare the efficacy of remission maintenance between infliximab “top-down” and “step-up” strategies in moderate to severe pediatric Crohn disease during 3 years. We also aimed to determine prognostic factors that may influence the relapse-free rate in these patients. Methods: The present study was a retrospective review of a prospective cohort, based on an infliximab treatment protocol for pediatric Crohn disease used at Samsung Medical Center. A total of 31 patients (group A) were treated with early infliximab induction (“top-down” strategy) and 20 patients (group B) refractory to conventional therapy underwent infliximab treatment (“step-up” strategy). The efficacy of infliximab treatment was assessed by relapse-free rate and remission period rate for 3 years. A total of 11 prognostic factors that may influence the relapse-free rate were further analyzed. Results: The relapse-free rates at 3 years were 35.5% (95% confidence interval [CI] 0.194–0.519) in group A and 15.0% (95% CI 0.037–0.335) in group B (Pu200a=u200a0.0094). Overall remission period rate for 3 years also showed a significant difference between the 2 groups (92.1%u200a±u200a7.2% vs 78.3%u200a±u200a16.6%; Pu200a=u200a0.005). Multivariable analysis revealed that the duration from the initial diagnosis to infliximab infusion was the only factor associated with relapse-free remission for 3 years (hazard ratiou200a=u200a1.077; 95% CI 1.025–1.131). Conclusions: “Top-down” strategy had a longer remission period compared with the “step-up” strategy in pediatric Crohn disease during a study period of 3 years, based on relapse-free rate and remission period rate. Earlier introduction of infliximab is recommended in pediatric patients with moderate to severe Crohn disease.

Relationship Between Azathioprine Dosage, 6-Thioguanine Nucleotide Levels, and Therapeutic Response in Pediatric Patients with IBD Treated with Azathioprine

Background:Azathioprine (AZA) is commonly used to treat IBD either alone or in combination with mesalazine. However, there are relatively few studies concerning the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in pediatric patients treated with both AZA and mesalazine. Methods:We retrospectively investigated the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in 137 pediatric patients with IBD treated with AZA using multilevel analysis. Additional factors affecting metabolite levels and therapeutic response were also analyzed. Results:A positive correlation was observed between AZA dosage and 6-thioguanine nucleotide (6-TGN) level (P < 0.0001). Variant TPMT genotype (P < 0.001) and concomitant use of mesalazine (P < 0.001) were predictors of higher 6-TGN levels. Leukopenia (P = 0.025) and lymphopenia (P = 0.045) were associated with higher levels of 6-TGN. Poor AZA compliance affected median 6-TGN levels (P < 0.001). The frequency of patients with median 6-TGN levels >235 pmol per 8 × 108 red blood cells was the highest in the sustained therapeutic response group (P = 0.015). Age, sex, IBD type, and duration of AZA therapy did not influence 6-TGN levels or therapeutic effect. Conclusions:AZA dosage is positively correlated with 6-TGN level. Higher 6-TGN levels are related to leukopenia, lymphopenia, and concurrent use of mesalazine. These results provide the rationale for monitoring metabolites to optimize drug dosing and minimize drug-related toxicity. In addition, maintenance of 6-TGN levels within a beneficial therapeutic range by direct monitoring should be helpful in attaining therapeutic efficacy, although this possibility should be verified in prospective studies.

Impact of Genetic Polymorphisms on 6-Thioguanine Nucleotide Levels and Toxicity in Pediatric Patients with IBD Treated with Azathioprine.

Background:Thiopurine-related toxicity results in discontinuation of therapy in up to 30% of patients with inflammatory bowel disease. Although thiopurine S-methyltransferase (TPMT) is implicated in toxicity, not all toxicity can be attributed to TPMT polymorphisms. We investigated the effects of polymorphisms of genes involved in thiopurine and folate metabolism pathways on 6-thioguanine nucleotide levels and toxicity. Methods:Retrospective clinical data and blood samples were collected from 132 pediatric patients with inflammatory bowel disease treated with azathioprine. Eighty-seven genetic polymorphisms of 30 genes were screened using the MassARRAY system, and 70 polymorphisms of 28 genes were selected for further analysis. Results:TPMT genotype (P < 0.001), concurrent use of mesalazine (P = 0.006), ABCC5 (rs2293001) (P < 0.001), ITPA (rs2236206 and rs8362) (P = 0.010 and P = 0.003), and ABCB1 (rs2032582) (P = 0.028) were all associated with the ratio of 6-thioguanine nucleotides to azathioprine dose. ADK (rs10824095) (P = 0.004, odds ratio [OR] = 6.220), SLC29A1 (rs747199) (P = 0.016, OR = 5.681), and TYMS (rs34743033) (P = 0.045, OR = 3.846) were associated with neutropenia. ABCC1 (rs2074087) (P = 0.022, OR = 3.406), IMPDH1 (rs2278294) (P = 0.027, OR = 0.276), and IMPDH2 (rs11706052) (P = 0.034, OR = 3.639) had a significant impact on lymphopenia. Conclusions:This study describes genetic polymorphisms in genes whose products may affect pharmacokinetics and which may predict the relative likelihood of benefit or risk from thiopurine treatment. These findings may serve as a basis for personalized thiopurine therapy in pediatric patients with inflammatory bowel disease, although our data need to be validated in further studies.

Initial location determines spontaneous passage of foreign bodies from the gastrointestinal tract in children.

Objective: The purpose of this study was to follow the natural course of spontaneous passage (SP) of ingested foreign bodies (FBs) in children. Methods: The medical records of 249 patients who ingested FBs were reviewed. In addition, they were studied by telephone questionnaires to follow up spontaneously passed FB. The factors associated with SP such as age, the type, size, and initial location of the FBs were analyzed. Results: Foreign bodies were spontaneously passed in 145 patients (58.2%), endoscopic removal was performed in 100 patients (40.2%), and operative removal was performed in 4 patients (1.6%). Most SP FBs were passed within 5 days. The SP rates (SPRs) according to the initial location were the following: 12.2% for the esophagus (P < 0.0001), 71.4% for the stomach, 85.7% for the small bowel, and 96.4% for the colon. There was no significant difference in the SPR according to age. When coins and disk batteries that required early endoscopic removal were excluded, the SPR was 63.4% for FBs less than 10 mm, 80.4% for FBs 10 to 20 mm, 72.8% for FBs 20 to 30 mm, and 50.0% for FBs more than 30 mm (P = 0.091). The initial location of the FB (odds ratio, 33.7; 95% confidence interval, 14.4-79.0) and the size of the FB (odds ratio, 3.5; 95% confidence interval, 1.0-11.6) were independent predictors of SP by multivariate analysis. Conclusions: Most FBs in the gastrointestinal tract are spontaneously passed without complication, and the initial location of FBs was found to be the main determining factor for SPR. Ingested FBs, in children, even sharp or relatively large FBs, can be spontaneously passed when they are located below the esophagus.

Norovirus: A Possible Cause of Pneumatosis Intestinalis

Objective: Pneumatosis intestinalis (PI) in children is associated with immunosuppression, mucosal disruption from trauma, obstructive pulmonary disease, congenital heart disease, and gastrointestinal infections. Our study is the first report of norovirus infection–associated PI. Patients and Methods: A retrospective review was performed in pediatric patients (older than 30 days) with PI from March 2005 to April 2009. Since December 2008, in addition to routine stool examinations, reverse-transcriptase polymerase chain reaction testing for calicivirus (norovirus and sapovirus), adenovirus, astrovirus, and enterovirus has been performed. Results: Twenty-seven patients with PI were identified. The median age was 1.4 (range 0.2–14.8 years). Seventeen patients (63.0%) were immunocompromised hosts. Pathogens were identified in 5 immunocompromised patients (5/27 and 5/8 since December 2008). Of note, norovirus was identified in 4 patients (80%, 4/5) during the cold weather season. The genotype of noroviruses in these patients was GII-4. Among 27 patients with PI, 10 patients (37.0%) developed PI in the spring and 11 (40.7%) in the winter. Twenty-four patients survived (88.9%, 24/27). None of the patients with norovirus or rotavirus infection died. Conclusions: Our data suggest that norovirus infection may contribute to the development of PI in immunocompromised hosts.

EPONYM. Sweet syndrome.

Sweet syndrome, also referred to as acute febrile neutrophilic dermatosis, is characterized by tender, red inflammatory nodules or papules that occur in association with infection, malignancy, connective tissue disease, or following exposure to certain drugs. Although drug-induced Sweet syndrome is rare, granulocyte colony-stimulating factor, all-trans-retinoic acid, and miscellaneous drugs have been implicated in causing this disorder in adults. In pediatric patients, granulocyte colony-stimulating factor, all-trans-retinoic acid, trimethoprim-sulfamethoxazole, and azathioprine have been implicated as potential causes of drug-induced Sweet syndrome. To date, six cases, including the patient reported here, have been reported in children.

Monitoring and Safety of Azathioprine Therapy in Inflammatory Bowel Disease

Azathioprine is the most common drug used to maintain clinical remission in inflammatory bowel disease. This drug is also important as a steroid-sparing agent in steroid-dependent and chronically active inflammatory bowel disease. Nevertheless, many questions remain concerning the optimal treatment regimens of azathioprine. The dose of azathioprine has to be reduced or the therapy has to be discontinued frequently because of drug-induced toxicity. In this review, we discuss monitoring of thiopurines, adverse events, malignant complications and how to use azathioprine safely and usefully.

The effects of three alternative treatment strategies after 8 weeks of proton pump inhibitor therapy for GERD in children

Objectives The purpose of this 24-week treatment study was to evaluate the effects of three treatment strategies after 8 weeks of lansoprazole therapy for gastroesophageal reflux disease in children. Design Open-labelled, uncontrolled, prospective study. Setting Samsung Medical Center, Seoul, Korea. Methods 37 erosive reflux disease (ERD) and 20 non-erosive reflux disease (NERD) patients were divided into three groups by symptom assessment at 8 weeks: (1) observation without treatment in the ‘symptoms-resolved’ group, (2) ‘on-demand’ treatment for an additional 16 weeks in the ‘symptoms-attenuated’ group and (3) continuous treatment in the ‘symptoms-persistent’ group. Results For ERD, six (100%) out of six patients in the ‘symptoms-resolved’ group remained improved at weeks 16 and 24. Sixteen (72.7%) out of 22 patients in the ‘symptoms-attenuated’ group had improvement of symptoms at 16 weeks, and 18 (81.8%) patients at 24 weeks. Six (66.7%) out of nine patients in the ‘symptoms-persistent’ group remained improved at weeks 16 and 24. For NERD, seven (100%) out of seven patients in the ‘symptoms-resolved’ group remained improved at weeks 16 and 24. Eight (80.0%) out of 10 patients in the ‘symptoms-attenuated’ group remained improved at week 16, and 10 (100.0%) patients at week 24. None out of three patients in the ‘symptoms-persistent’ group remained improved at weeks 16 and 24. Conclusions The selection of each alternative for long-term management according to the results of the assessment of symptoms at week 8 was useful and well tolerated. ‘On-demand’ therapy was equally effective. The 16-week therapy had the same efficacy as the 24-week therapy with regard to long-term lansoprazole treatment.

Change in the treatment strategy for pediatric Crohn's disease

Crohns disease is characterized by chronic inflammation involving any portion of the gastrointestinal tract. Treating Crohns disease is a major challenge for clinicians, as no curative therapy currently exists. Pediatric Crohns disease is characterized by frequent relapses, a wide extent of disease, a high prevalence of extraintestinal manifestations, and a severe clinical course. The classic therapeutic approach is known as the step-up strategy, and follows a progressive course of treatment intensification as disease severity increases. Although this approach is usually effective for symptom control, many patients become either resistant to or dependent on corticosteroids. The efficacy of infliximab suggests that, rather than a progressive course of treatment, early intense induction may reduce complications associated with conventional treatment and improve quality of life. Intensive early therapy with infliximab is known as the top-down strategy. Such therapy offers the potential for altering the natural history of Crohns disease, and is changing treatment paradigms. However, the relatively new concept of an early aggressive or top-down treatment approach is not yet widely accepted, especially in pediatric patients. The results of our current study demonstrate that early and intensive treatment of pediatric Crohns disease patients with infliximab, at initial diagnosis, was more effective for maintaining remission and reducing flares.